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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus belonging to the coronavirus family responsible for coronavirus disease 2019 (COVID-19). It primarily affects the pulmonary system, which is the target of chronic obstructive pulmonary disease (COPD), for which many new compounds have been developed. In this study, phosphodiesterase 4 (PDE4) inhibitors are being investigated. The inhibition of PDE4 enzyme produces anti-inflammatory and bronchodilator effects in the lung by inducing an increase in cAMP concentrations. Piclamilast and rolipram are known selective inhibitors of PDE4, which are unfortunately endowed with common side effects, such as nausea and emesis. The selective inhibition of the phosphodiesterase 4B (PDE4B) subtype may represent an intriguing technique for combating this highly contagious disease with fewer side effects. In this article, molecular docking studies for the selective inhibition of the PDE4B enzyme have been carried out on 21 in-house compounds. The compounds were docked into the pocket of the PDE4B catalytic site, and in most cases, they were almost completely superimposed onto piclamilast. Then, in order to enlarge our study, drug-likeness prediction studies were performed on the compounds under study.

Mitochondrial carriers transport organic acids, amino acids, nucleotides and cofactors across the mitochondrial inner membrane. These transporters consist of a three-fold symmetric bundle of six transmembrane α-helices that encircle a pore with a central substrate binding site, whose alternating access is controlled by a cytoplasmic and a matrix gate (C- and M-gates). The C- and M-gates close by forming two different salt-bridge networks involving the conserved motifs [YF][DE]XX[KR] on the even-numbered and PX[DE]XX[KR] on the odd-numbered transmembrane α-helices, respectively. We have investigated the effects on transport of mutating the C-gate charged residues of the yeast NAD+ transporter Ndt1p and performed molecular docking with NAD+ and other substrates into structural models of Ndt1p. Double-cysteine substitutions and swapping the positions of the C-gate charged-pair residues showed that all of them contribute to the high transport rate of wild-type Ndt1p, although no single salt bridge is essential for activity. The in silico docking results strongly suggest that both the C-gate motif mutations and our previously reported M-gate mutations affect gate closing, whereas those of the M-gate also affect substrate binding, which is further supported by molecular dynamics. In particular, NAD+ most likely interferes with the cation-π interaction between R303-W198, which has been proposed to exist in the Ndt1p M-gate in the place of one of the salt bridges. These findings contribute to understanding the roles of the charged C- and M-gate residues in the transport mechanism of Ndt1p. [ABSTRACT FROM AUTHOR]

Citrate, which is obtained from oxaloacetate and acetyl-CoA by citrate synthase in mitochondria, plays a key role in both normal and cancer cell metabolism. In this work, we investigated the effect of 10 mM extracellular citrate supplementation on HepG2 cells. Gene expression reprogramming was evaluated by whole transcriptome analysis using gene set enrichment analysis (GSEA). The transcriptomic data were validated through analyzing changes in the mRNA levels of selected genes by qRT-PCR. Citrate-treated cells exhibited the statistically significant dysregulation of 3551 genes; 851 genes were upregulated and 822 genes were downregulated. GSEA identified 40 pathways affected by differentially expressed mRNAs. The most affected biological processes were related to lipid and RNA metabolism. Several genes of the cytochrome P450 family were upregulated in treated cells compared to controls, including the CYP3A5 gene, a tumor suppressor in hepatocellular carcinoma (HCC) that plays an important protective role in HCC metastasis. The citrate-induced dysregulation of cytochromes could both improve the effectiveness of chemotherapeutics used in combination and reduce the aggressiveness of tumors by diminishing cell migration and invasion. [ABSTRACT FROM AUTHOR]

S‐adenosyl‐L‐methionine (SAM) is a coenzyme and the most commonly used methyl‐group donor for the modification of metabolites, DNA, RNA and proteins. SAM biosynthesis and SAM regeneration from the methylation reaction product S‐adenosyl‐L‐homocysteine (SAH) take place in the cytoplasm. Therefore, the intramitochondrial SAM‐dependent methyltransferases require the import of SAM and export of SAH for recycling. Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1‐2 in plants. In mitochondria SAM is used by a vast number of enzymes implicated in the following processes: the regulation of replication, transcription, translation, and enzymatic activities; the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin. Mutations in SLC25A26 and mitochondrial SAM‐dependent enzymes have been found to cause human diseases, which emphasizes the physiological importance of these proteins. [ABSTRACT FROM AUTHOR]

Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD+, which are all structurally similar to nucleotides and derived from different B‐vitamins. These mitochondrial cofactors bind more or less tightly to their enzymes and, after having been involved in a specific reaction step, are regenerated, spontaneously or by other enzymes, to return to their active form, ready for the next catalysis round. Disease‐causing mutations in the mitochondrial cofactor carrier genes compromise not only the transport reaction but also the activity of all mitochondrial enzymes using that particular cofactor and the metabolic pathways in which the cofactor‐dependent enzymes are involved. The mitochondrial transport, metabolism and diseases of the cofactors thiamine pyrophosphate, coenzyme A, FAD and NAD+ are the focus of this review. [ABSTRACT FROM AUTHOR]

S‐adenosyl‐L‐methionine (SAM) is a coenzyme and the most commonly used methyl‐group donor for the modification of metabolites, DNA, RNA and proteins. SAM biosynthesis and SAM regeneration from the methylation reaction product S‐adenosyl‐L‐homocysteine (SAH) take place in the cytoplasm. Therefore, the intramitochondrial SAM‐dependent methyltransferases require the import of SAM and export of SAH for recycling. Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1‐2 in plants. In mitochondria SAM is used by a vast number of enzymes implicated in the following processes: the regulation of replication, transcription, translation, and enzymatic activities; the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin. Mutations in SLC25A26 and mitochondrial SAM‐dependent enzymes have been found to cause human diseases, which emphasizes the physiological importance of these proteins. [ABSTRACT FROM AUTHOR]